JP2006523201A - Process for the enantioselective preparation of sulfoxide derivatives - Google Patents

Abstract

The present invention relates to a process for the enantioselective preparation of substituted derivatives of sulfoxides, in particular to a process for the enantioselective preparation of compounds such as enantiomers of tenatoprazole and other similar compounds.
The present invention relates to a process for the enantioselective preparation of substituted sulfoxide derivatives. This method employs a general formula (I): A-CH2-SB (I) [where A = variously, using an oxidizing agent in the presence of a tungsten or vanadium based catalyst as well as a chiral ligand. The sulfide of the substituted pyridyl nucleus, B = heterocycle with benzimidazole or imidazopyridyl nucleus], followed by the formation of a salt with a base, if necessary, to form a sulfoxide : Obtaining A-CH2-SO-B (Ia). The above applies to the enantioselective preparation of compounds such as tenatoprazole and other comparable sulfoxide enantiomers.

Description

  The present invention relates to a process for the enantioselective preparation of substituted derivatives of sulfoxides, and in particular to a process for the enantioselective preparation of compounds such as enantiomers of tenatoprazole and other similar compounds.

  Sulphoxides, particularly some derivatives of pyridinyl-methyl-sulfinylbenzimidazoles, are known to be useful in therapy and have properties that inhibit the proton pump, ie, inhibit gastric acid secretion, gastric and duodenal ulcers Acts as an effective drug in treating The first known derivatives of these series of proton pump inhibitors are omeprazole or 5-methoxy-2-[[(4-methoxy-3,5-dimethyl) as described in EP-005129. -2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, which has the property of inhibiting the secretion of gastric acid and is widely used as an anti-ulcer agent in human therapy. Other derivatives of benzimidazole are known by their generic names such as rabeprazole, pantoprazole, lansoprazole, all showing structural similarity and pyridinyl-methyl-sulfinyl-benz. It belongs to the group of imidazoles.

  Tenatoprazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] imidazo [4,5-b] pyridine, is described in EP 254588. It is described in the specification. This is also part of a drug that is considered a proton pump inhibitor and can be used in treating gastro-esophageal reflux, digestive bleeding and dyspepsia.

  All of these compounds are sulfoxides exhibiting asymmetry at the sulfur atom, and thus take the form of a racemic mixture consisting of two enantiomers. It may be useful to selectively separate them into the R and S configurations with specific properties that can differ significantly, or in the form of either one of the (+) or (-) enantiomers, respectively. is there.

  Selectively or preferentially, there are several methods for preparing any of these sulfoxide enantiomers, in particular omeprazole and its enantiomers in the S configuration, esomeprazole, and also its salts such as sodium or magnesium salts. It is described in the scientific literature.

  For example, EP 652872 uses magnesium esters of the (−) enantiomer of omeprazole by using esters containing chiral acyloxymethyl groups, separating diastereoisomers and solvolysis in alkaline solution. Describes a method of preparing U.S. Pat. No. 5,776,765 describes a method using stereoselective bioreduction of a racemic mixture of sulfides in the corresponding sulfoxide by using a microorganism containing DMSO reductase, thereby A mixture can be obtained in which the (−) enantiomer is considerably enriched compared to the (+) enantiomer. U.S. Pat. No. 5,948,789 discloses the oxidation of the corresponding sulfide with hydrogen peroxide in the presence of a titanium complex and a chiral ligand, in particular the (−) enantiomer of omeprazole or its sodium salt. It relates to enantioselective preparation. The method described in this patent makes it possible to obtain a mixture enriched with either the (−) and (+) enantiomers, depending on the ligand used.

  Studies done so far by the applicant have shown that sulfoxides under good purity and yield conditions can be obtained by enantioselectively oxidizing the corresponding sulfides in the presence of special tungsten or vanadium based catalysts. It has been found that the enantiomers of derivatives, in particular tenatoprazole, can be obtained enantioselectively.

  The present invention therefore relates to a process for the enantioselective preparation of sulfoxide derivatives exhibiting asymmetry at the sulfur atom to yield either enantiomer in a sufficient level of yield and purity.

  In particular, the present invention relates to a method of preparation that can generate the (−) and (+) enantiomers of tenatoprazole significantly enantioselectively. The term “substantially enantioselectively” as used above means that the desired enantiomer is obtained in a selective or predominant amount over other enantiomers.

In the preparation method of the present invention, an oxidant is used in the presence of a catalyst based on tungsten or vanadium and a chiral ligand, and the following general formula (I):
_{A-CH 2 -S-B (} I)
[Wherein A is a pyridyl nucleus which is variously substituted and B is a heterocyclic residue having a benzimidazole or imidazopyridyl nucleus]
Enantioselective oxidation of the sulfide represented by is followed by salt formation with a base if necessary.

  In the general formula (I), A is preferably a pyridyl group or a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, A methyl or ethyl group, amino, alkylamino or dialkylamino group substituted by one or more halogen atoms (wherein the alkyl component is linear or branched and has 1 to 5 carbon atoms) P) is a pyridyl group having one or more substituents selected from: B is one or more linear or branched alkyl groups of 1 to 6 carbon atoms, if necessary; Substituted by straight or branched alkoxy groups of 1 to 6 carbon atoms, preferably substituted at one or more carbons by methyl, ethyl, methoxy or trihalomethyl groups Benzimidazole or imidazo are - [4,5-b] - represents a heterocycle selected from pyridyl group.

  In the above general formula (I), A is preferably a 2-pyridyl group substituted by one or more methyl, ethyl, methoxy or trifluoromethyl groups, in particular 4-methoxy-3,5- A dimethyl-2-pyridyl group. B is preferably a 5-methoxy-1H-benzimidazolyl group or a B5-methoxy-imidazo- [4,5-b] -pyridyl group.

  The sulphide corresponding to formula (I) above is prepared according to several methods described in the literature, for example according to the methods described in EP 254588 and EP 103553. Is a known product.

Thus, the following formula:
_{A-CH 2 -SO-B (} Ia)
A sulfoxide having [wherein A and B have the above definitions] is obtained.

The oxidizing agent used in the process of the present invention is preferably a peroxide, such as hydrogen peroxide, or a hydroperoxide, such as cumene or t-butyl hydroperoxide. In an advantageous implementation, for example, a high concentration of hydrogen peroxide of more than 30% or hydrogen peroxide complexed with urea, referred to hereinafter as “UHP” (UHP: urea hydrogen peroxide H ₂ NCONH ₂ .H ₂ O ₂ ) is used.

Catalysts based on tungsten or vanadium are an essential element of the process of the present invention, which can cause the reaction to yield the desired derivative in good yield. In the present invention, catalysts such as Voxovanadium complexes prepared from tungsten derivatives such as vanadium acetylacetonate VO (acac) ₂ or tungsten trioxide WO ₃ are preferably used. Such catalysts are commercially available. Complexes prepared from vanadium sulfate VOSO ₄ can also be used.

  The selection of the ligand is another characteristic element of the present invention because it allows the reaction to be selectively directed to the desired enantiomer.

  In the present invention, in the case of vanadium-based catalysts, the ligand is preferably tridentate.

The ligand is preferably of the following general formula (II):
_{RO-CR 1 R 2 -CR 3} R 4 -NR 5 R 6 (II)
[In the above formula,
R is a hydrogen atom or a straight or branched alkyl group of 1 to 6 carbon atoms or an aryl or heteroaryl group;
R ₁ to R ₄ may be the same or different and optionally have a straight chain of 1 to 6 carbon atoms having heteroatoms such as sulfur, nitrogen and oxygen and / or optionally substituted with an amino group or Represents a branched alkyl group; an aryl group; an alkylaryl group; an alkoxycarbonyl group; a heteroaryl group or a heterocycle; a heteroarylalkyl or heterocycloalkyl group, provided that the ligand is one or two asymmetric centers R ₁ must not be the same as R ₂ and / or R ₃ must not be the same as R ₄ ;
R ₁ and R ₂ may both represent a carbonyl group C═O;
R ₁ and R ₃ or R ₂ and R ₄ are both carbocycles having 5 or 6 carbon atoms or bicyclic rings having 9 to 10 carbon atoms, one of which may be aromatic May form a system;
Similarly, R ₄ and R ₅ may form a 5- or 6-membered heterocycle having a nitrogen atom;
R ₅ and R ₆ may be the same or different and represent a straight-chain or branched alkyl group having 1 to 6 carbon atoms or a 5- or 6-membered carbocycle, or a heterocycle with a nitrogen atom bonded thereto. Or form a ring; or R ₅ and R ₆ together with nitrogen represent a —N═CHAr double bond, where Ar may be substituted with 1 to 3 groups, preferably hydroxyl An aryl residue having a group]
Can be represented by

  Ar is preferably a 2'-hydroxyphenyl group optionally substituted at the aryl group.

R ₁ and R ₃ or R ₂ and R ₄ preferably represent a hydrogen atom, wherein R ₂ and R ₄ or R ₁ and R ₃ are each a straight or branched chain of 1 to 6 carbon atoms Alkyl groups, aryl groups, or together form a carbocycle having 5 or 6 carbon atoms, or a bicyclic system having 9 or 10 carbon atoms, one of which may be aromatic To do.

In the present invention:
“Aryl group” preferably means a monocyclic or polycyclic ring system having one or more aromatic rings, including phenyl, naphthyl, tetrahydronaphthyl, indanyl and binaphthyl groups. The aryl group is a hydroxyl group, a linear or branched alkyl group containing 1 to 4 carbon atoms such as methyl, ethyl, propyl or preferably t-butyl, a nitro group, a (C ₁ -C ₄ ) alkoxy group. Optionally substituted by 1 to 3 substituents independently selected from halogen atoms such as chlorine, bromine or iodine;
“Arylalkyl group” preferably means an aryl group appended to an alkyl group containing from 1 to 4 carbon atoms;
“Alkoxycarbonyl group” preferably means an alkoxy group containing from 1 to 4 carbon atoms appended to a carbonyl group, for example methoxycarbonyl;
"Heteroaryl group" preferably means an aryl group containing 1 to 3 heteroatoms such as nitrogen, sulfur or oxygen, and includes pyridyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl and the like;
“Heterocycle” or “heterocyclic group” preferably means a 5- or 6-membered ring containing 1 to 3 heteroatoms such as sulfur, nitrogen or oxygen. This definition further includes bicyclic rings, wherein the heterocyclic group defined above is fused with a phenyl group, a cyclohexane group or another heterocyclic ring. Among the heterocyclic groups, mention may be made of imidazolyl, indolyl, isoxazolyl, furyl, pyrazolyl, thienyl and the like;
“Heteroarylalkyl” preferably means an alkyl group containing from 1 to 4 carbon atoms, preferably a heteroaryl group attached to methyl;
“Heterocyclic alkyl group” preferably means an alkyl group containing from 1 to 4 carbon atoms, preferably a heterocyclic group attached to methyl, for example 4-imidazolylmethyl.

Particularly preferably, the ligand of formula (II) is:
Amino-alcohols of formula (III)

[Wherein R ₁ , R ₂ , R ₃ and R ₄ are defined in the same manner as described above. Among the amino alcohols of the formula (III), L- (S-(+)-) or D-valinol (R-(−)-2-amino-3-methyl-1-butanol), Rt-leucinol ( R-(-)-2-amino-3,3-dimethyl-1-butanol), St-leucinol (S-(+)-2-amino-3,3-dimethyl-1-butanol) and (1S , 2R)-(−)-or (1R, 2S)-(+)-1-amino-2-indanol]
Amino-ether of formula (IV)

[Wherein R, R ₁ , R ₂ , R ₃ and R ₄ are defined as above],
Amino acids of formula (V)

[Wherein R ′ has the definition of R ₃ or R ₄ described above. Among the amino acids of formula (V), mention may be made of L-valine or D-valine, L-phenylalanine or D-phenylalanine, L-methionine or D-methionine, L-histidine or D-histidine and L-lysine or D-lysine. be able to],
Amino-esters of the formula (VI)

[Wherein R ′ has the definition of R ₃ or R ₄ and R ″ has the definition of R as defined above].

  Preferably, these amino-alcohols, amino-ethers, amino acids or amino-esters of the formulas (III), (IV), (V) and (VI) are used in order to obtain particularly advantageous ligands, ie Schiff bases. Aldehyde of salicylic acid of formula (VII):

[Wherein R ₇ is a hydroxyl group, methyl, ethyl, propyl or a linear or branched alkyl group containing 1 to 4 carbon atoms such as t-butyl, preferably nitro group, (C _1- C ₄ ) represents an alkoxy group and 1 to 2 substituents independently selected from halogen atoms such as chlorine, bromine or iodine.

In the framework of the present invention, a ligand of formula (II) is particularly preferred, which ligand is derived from an amino alcohol of formula (III), where
R ₅ and R ₆ together with the nitrogen atom represent a double bond —N═CHAr, where Ar is an aryl group comprising 1 to 3 substituents and at least one hydroxyl group, Ar being , Preferably a phenyl group,
R ₁ and R ₃ or R ₂ and R ₄ represent a hydrogen atom, wherein R ₂ and R ₄ or R ₁ and R ₃ are each independently a straight chain containing 1 to 6 carbon atoms Or a branched alkyl group, preferably a t-butyl group, or both a 5 to 6 carbon ring or a bicyclic ring consisting of 9 or 10 carbon atoms, one of which may be aromatic Forms a system, preferably indanyl.

In the present invention, the ligand can preferably be selected depending on the catalyst used, for example, in the case of tungsten, the ligand can be used depending on the enantiomer being sought, The ligands are:
Belong to the family of quince skin alkaloids such as quinine, quinidine, dihydroquinidine (DHQD) or dihydroquinine (DHQ),
For alkaloids such as hydroquinine 2,5-diphenyl-4,6-pyridinediyl diether (DHQ) ₂ -PYR or hydroquinidine 2,5-diphenyl-4,6-pyridinediyl diether (DHQD) ₂ -PYR Derived from.

  In the case of a vanadium-based catalyst, a ligand represented by the above formula (II) having a substituent at the nitrogen atom, for example, a substituted aldehyde of salicylic acid and a Schiff base derived from a chiral amino-alcohol is preferably used. .

  Usually, in the case of vanadium-based catalysts as vanadium acetylacetonate, using a ligand derived from an amino-alcohol or amino-ether of formula (III) or (IV), respectively, as defined above, preferable. Conversely, in the case of catalysts based on vanadium as vanadium sulfate, ligands derived from the amino acids or amino esters of formula (V) or (VI) respectively defined above are preferably used.

  For example, in the case of a vanadium-based catalyst, preferably vanadium acetylacetonate, the ligand 2,4-di-tert-butyl-6- [that can be selectively directed to the enantiomer seeking the reaction. 1-R-hydroxymethyl-2-methyl-propylimino) -methyl] -phenol and its isomer 2,4-di-t-butyl-6- [1-S-hydroxymethyl-2-methyl-propylimino) -Methyl] -phenol is particularly preferred. By using 2,4-di-t-butyl-6- [1-R-hydroxymethyl-2-methyl-propylimino) -methyl] -phenol, 5-methoxy-2-[[4-methoxy- The oxidation reaction of 3,5-dimethyl-2-pyridyl) methyl] thio] imidazo [4,5-b] pyridine can be selectively directed to give S-tenatoprazole as shown below.

  Similarly, in the case of vanadium-based catalysts, preferably as vanadium acetylacetonate, the ligand (1R, 2S) -1- [2-hydroxy-3,5-di-t derived from aminoindanol as amino alcohol -Butyl-benzylidene) -amino] -indan-2-ol is particularly preferred.

  For example, by using the above ligand, an oxidation reaction of 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] imidazo [4,5-b] pyridine is carried out. By selectively directing, the S-thesodium prazole shown below can be selectively obtained.

  Under operating conditions, the ligand is preferably tridentate and forms an asymmetric complex with the metal catalyst, wherein the metal is oxidized by an oxidizing agent.

  In a characteristic form of the invention, methanol, tetrahydrofuran, methylene chloride, acetonitrile, toluene, acetone, chloroform, alone or mixed in a solvent, preferably in a solvent mixture, in a neutral or weakly basic medium, The reaction can be carried out by selecting a sulfide specific solvent and a ligand specific solvent selected from the group consisting of DMF (dimethylformamide) or NMP (N-methylpyrrolidinone). The base that can be used may be a tertiary amine such as pyridine, di-isopropylethylamine or triethylamine.

  Alternatively, the process can be carried out without the addition of a base, but treatment in an acidic medium is preferably avoided as it can result in degradation of the final product.

  In the present invention, it is particularly advantageous to use vanadium-based catalysts and ligands in the form of acetonitrile solutions, in which the sulfide is dissolved in a chlorinated solvent such as methylene chloride and then these 2 The seed solution is mixed to carry out the oxidation.

  The oxidation reaction is conveniently carried out at low temperature or room temperature. It is advantageous to induce at a temperature of 0 to 10 ° C, preferably about 4 to 5 ° C to promote enantioselectivity.

  The method of the present invention is particularly advantageous because both oxidizers and catalysts are widely commercially available, inexpensive and easy to process. Furthermore, the catalyst can be used effectively and in very small amounts. The yields of the enantiomers obtained are excellent and, furthermore, the catalyst and ligand can usually be reused under good conditions without any loss of enantiomeric excess.

  The process of the invention is particularly advantageous in preparing the enantiomers of tenatoprazole which can be represented by the general formula:

For example, in the process of the invention, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) with hydrogen peroxide in the presence of tungsten trioxide and (DHQD) ₂ -PYR. The enantioselective oxidation of methyl] thio] imidazo [4,5-b] pyridine was carried out very advantageously to give (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2 -Pyridyl) methyl] sulfinyl] imidazo [4,5-b] pyridine can be obtained.

  In particular, 2,4-di-t-butyl-6- [1-R-hydroxy-methyl-2-methyl-propylimino) -methyl] -phenol or (1R, 2S) -1- [2-hydroxy- A vanadium-based catalyst is used in the form of an acetonitrile solution with a ligand consisting of 3,5-di-tert-butyl-benzylidene) -amino] -indan-2-ol, whereas the sulfide is in the form of a methylene chloride solution. It is noted that the (−) enantiomer having the S-configuration can be obtained in excellent purity and yield conditions by oxidation of the sulfides when in acetone or NMP respectively.

  Conversely, 2,4-di-t-butyl-6- [1-S-hydroxy-methyl-2-methyl-propylimino) -methyl] -phenol or (1S, 2R) -1- [2- By using hydroxy-3,5-di-t-butyl-benzylidene) -amino] -indan-2-ol, the (+) isomer with R-configuration is obtained with excellent selectivity and yield conditions. You can also.

  The (−) and (+) enantiomers of tenatoprazole can be used in the form of salts, in particular alkali metal or alkaline earth metal salts, for example in the form of sodium, potassium, lithium, magnesium or calcium salts. . These salts can be obtained from the previously isolated (-) or (+) enantiomer of tenatoprazole by chlorination by prior art methods, for example, by the action of a basic inorganic reagent containing an alkali or alkaline earth counterion. Obtainable.

  Of course, it is also possible to obtain the (−) and (+) enantiomers from the racemic mixture in completely pure optical form by preparative column chromatography, eg chiral or HPLC chromatography, using any suitable separation method. it can. The enantiomer thus obtained can be used as a control. “Pure optical form” means that the (−) enantiomer contains substantially no (+) enantiomer or only a trace amount thereof, and vice versa. If necessary, chlorination with a base is then carried out in a suitable solvent to form a salt, in particular an alkali or alkaline earth metal salt.

  The principles of chiral chromatography methods are well known and are based on the affinity differences present in the (+) and (−) enantiomers and the stationary phase chiral selector. By this method, enantiomers can be separated with sufficient yield.

  The (−) enantiomer of tenatoprazole is (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4,5-b] pyridine or Corresponds to (−)-tenatoprazole. This form can be determined by optical rotation measurements using standard techniques. For example, the optical rotation angle of (−)-tenatoprazole is levorotatory in dimethylformamide and acetonitrile, and its melting point is 130 ° (decomposition).

  In the case of chiral separation of tenatoprazole, the racemic mixture used as starting material can be obtained using known methods, for example by the method described in EP 254588. For example, the corresponding sulfide produced by condensation of thiol and pyridine using an oxidizing agent such as perbenzoic acid, preferably in the presence of a base such as potassium hydroxide, in a suitable solvent such as ethanol, under heating. Can be prepared by treating.

  In treating the following diseases, tenatoprazole (-) and (+) in a standard form suitable for the selected route of administration, eg, oral or parenteral route, preferably oral or intravenous route. ) Enantiomers can be administered.

  For example, tablets or capsule formulations or other oral solutions or emulsions or tenatoprazole salts containing any of the (−) and (+) enantiomers of tenatoprazole as active substances together with standard pharmaceutically acceptable substances A solution for parenteral administration containing can be used. The enantiomeric salt of tenatoprazole can be selected from, for example, sodium, potassium, lithium, magnesium or calcium salts.

  Symptoms and lesions of gastro-esophageal reflux, digestive hemorrhagic resistance to other proton pump inhibitors in the manufacture of drugs for the treatment of digestive disorders, particularly those where inhibition of gastric acid is strong and required for a long time (-) And (+) enantiomers of tenatoprazole obtained using the method of the present invention can be used in treating.

  Depending on the patient's condition and the severity of the condition, the physician will determine the dosing regime. Usually, tenatoprazole (−) or (+) enantiomer is 10 to 120 mg, preferably 20 to 80 mg per day.

  To illustrate the invention, examples of preparing enantiomers are described below, but these do not limit the application.

Example 1 Preparation of (S)-(−)-tenatoprazole 10 g WO ₃ maintained at a temperature of 4 to 5 ° C. with stirring, 73 g of (DHQD) ₂ -PYR, 3.5 L of THF and 5-methoxy-2 -[[(4-Methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] imidazo [4,5-b] pyridine (330 g) was placed in a 5 L flask, and 30 mL of 30% hydrogen peroxide was added thereto. Add. The reaction medium is maintained under stirring for 48 hours. The catalyst is then filtered and the filtrate is diluted with 10 L of methylene chloride at room temperature.

  The organic phase is washed with water, then dried and concentrated under reduced pressure. 242 g of the desired enantiomer are obtained with an enantiomeric excess of more than 90% (yield 70%).

Recrystallization in methanol / water or DMF / ethyl acetate mixtures gives enantiomers in excess of 99% enantiomers. The enantiomeric excess is determined by high performance liquid chromatography using a CHIRALPAK AS-H 20 μm (250 × 4.6 mm) column at 25 ° C., the eluent is acetonitrile (1 mL / min), and the detection is U.S. at 305 nm. V. Perform by spectroscopy. The retention time of the (S)-(−) isomer is equal to 7.7 minutes and the retention time of the (R)-(+) isomer is equal to 5.2 minutes.
T _F : 129 to 130 ° C
[Α] ²⁰ _D : -186.6 (c0, 1, DMF)
Elemental analysis:

UV spectrum (methanol-water): [lambda] _max : 272 nm ([epsilon] = 6180), 315 nm ([epsilon] = 24877).

Infrared (KBr): 3006, 1581, 1436, 1364, 1262, 1026, 1040 and 823 cm ⁻¹ .

RMN ¹ H (DMSO d ₆ , reference: TMS) δ (ppm): 2.20 (s, 6H), 3.70 (s, 3H), 3.91 (s, 3H), 4.69-4. 85 (m, 2H), 6.80 (d, J8.5Hz, 1H), 7.99 (d, J8.5Hz, 1H), 8.16 (s, H), 13.92 (s, 1H) .

RMN ¹³ C (DMSO d ₆ , Reference: TMS) δ (ppm): 13.2; 15.0; 56.6; 60.8; 62.6; 107.2; 129.5; 130.4; .9; 135.1; 150.5; 151.4; 156.9; 160.7; 163.0; 166.6.

Example 2 (R) - (+) - using the same conditions as described in example 1 tenatoprazole, however, instead of _(DHQD) a 2 PYR _(DHQ) 2 -PYR, 120 mL of hydrogen peroxide was added to the same amount of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] -imidazo [4 as described in Example 1. , 5-b] pyridine and react using the same catalyst.

  Thus, after recrystallization in a DMF / ethyl acetate mixture, the desired (+) enantiomer is obtained with an enantiomeric excess of over 99%.

The optical rotation measured with a polarimeter in dimethylformamide is [D] ²⁰ _D = + 186 °.

The physical and spectral constants of (R)-(+)-tenatoprazole are the same as those of (S)-(−)-tenatoprazole, except that the optical rotation is: [α] ²⁰ _D : +185.9 (c0.1, DMF).

Example 3 Preparation of (S)-(−)-omeprazole (esomeprazole) Using the operating conditions of Example 1, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] -1H-benz instead of pyridyl) methyl] thio] -imidazo [4,5-b] pyridine When imidazole is used, the desired product (esomeprazole) is obtained with an enantiomeric excess of about 90% (yield 72%).

  The product obtained matches the analytical data obtained in the literature.

Example 4 Preparation of (S)-(−)-Tenatoprazole 3 L of methylene chloride followed by 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] -imidazo 360 g of [4,5-b] pyridine is introduced into a 5 L flask. The mixture is left under stirring for 30 minutes at room temperature.

  One drop of 700 ml of acetonitrile, 5.22 g of 2,4-di-t-butyl-6- [1-S-hydroxymethyl-2-methyl-propylimino) -methyl] phenol and then 2.90 g of vanadyl acetylacetoacetate Add dropwise to a 2 L flask. The mixture is kept at room temperature under stirring. After 30 minutes under stirring, this mixture is added to the above.

Under stirring at room temperature over 20 hours, 135 ml of 30% hydrogen peroxide is added to the mixture. After separation of the aqueous phase, the organic phase is washed twice with water, then dried and concentrated under reduced pressure. 283 g of the desired enantiomer are obtained with an enantiomeric excess of more than 80% (yield 75%). Two successive recrystallizations in methanol / water or DMF / ethyl acetate mixtures give enantiomers with enantiomeric excess greater than 99%.
T _F : 127.5 ° C
[Α] ²⁰ _D : -182 (c0.1, DMF).

Example 5 Preparation of (R)-(+)-tenatoprazole The instructions of Example 4 are followed except that 2,4-di-tert-butyl-6- [1-R-hydroxymethyl-2-methyl-propyl. Imino) -methyl] -phenol is replaced with 2,4-di-t-butyl-6- [1-S-hydroxymethyl-2-methyl-propylimino) -methyl] -phenol.

The desired enantiomer is then obtained.
[Α] ²⁰ _D : +185.9 (c0, 1, DMF).

Example 6 Preparation of (S)-(−)-Tenatoprazole NMP1.2L followed by 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] imidazo [ 240 g of 4,5-b] pyridine are introduced into a 5 L flask. The mixture is left for 1 hour 30 minutes at room temperature under stirring.

  18 mL of NMP, 2.9 g of (1R, 2S) -1- [2-hydroxy-3,5-di-tert-butyl-benzylidene) -amino] -indan-2-ol, and then 1.9 g of vanadium acetylacetonate were added. In turn, introduce into a 50 mL round bottom flask. The mixture is stirred at room temperature. After stirring for 1 hour 30 minutes, this solution is added to the reaction mixture.

  While stirring, 95 mL of 30% hydrogen peroxide was added to the mixture at room temperature over 20 hours. The reaction mixture is precipitated by adding 500 mL of water.

  The precipitate is collected by filtration and then added to 5 L of chloroform. The organic phase was washed twice with water, then dried and concentrated in vacuo. 126 g of the desired enantiomer are obtained with an enantiomeric excess of more than 30% (yield 50%). Performing multiple recrystallizations in a DMF / ethyl acetate mixture gives enantiomers with an enantiomeric excess of over 99%.

Example 7 Preparation of (S)-(−)-Tenatoprazole 3.7 L acetone, then 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio]- 30 g of imidazo [4,5-b] pyridine is introduced into a 10 L flask. The mixture is left under stirring for 30 minutes at room temperature.

  100 mL of 30 mL of acetonitrile, 1.66 g of (1R, 2S) -1- [2-hydroxy-3,5-di-tert-butyl-benzylidene) -amino] -indan-2-ol, and then 1.19 g of vanadium acetylacetonate Into a round bottom flask. The mixture is stirred at room temperature. After stirring for 1 hour 30 minutes, this suspension is added to the reaction mixture.

Under stirring, 10 g of urea-H ₂ O ₂ dissolved in 7 mL of water and 50 mL of acetone are added to this mixture over 6 hours. The mixture is then left at room temperature for 12 hours. Add sodium metabisulfite solution, then 20% ammonia solution and acetone and concentrate. After washing with 100 mL of chloroform, the aqueous phase is recovered and then neutralized with acetic acid. Extraction with 200 mL of chloroform is carried out twice. After separating the aqueous phase, the organic phase is dried and concentrated under reduced pressure. 19 g of the desired enantiomer are obtained with an enantiomeric excess of more than 50% (yield 60%). Multiple crystallizations in a DMF / ethyl acetate mixture give enantiomers in excess of 99% enantiomeric excess.

Example 8 Preparation of (S)-(−)-Tenatoprazole Acetone 4L, then 5-methoxy-2-[[4-methoxy-3,5-dimethyl] -2-pyridyl) methyl] thio] imidazo [4 , 5-b] pyridine 30 g is introduced into a 10 L flask. The mixture is left under stirring for 30 minutes at room temperature.

  25 mL of acetonitrile, 1.66 g of (1R, 2S) -1- [2-hydroxy-3,5-di-t-butyl-benzylidene) -amino] -indan-2-ol and then 1.19 g of vanadium acetylacetonate In this order, introduce into a 100 mL round bottom flask. The mixture is stirred at room temperature. After stirring for 1 hour 30 minutes, this suspension is added to the reaction mixture.

Under stirring, 30 g of sodium sulfate, 10 g of urea-H ₂ O ₂ dissolved in 7 mL of water and 50 mL of acetone are added to this mixture over 6 hours. The mixture is then left under stirring for 12 hours at room temperature. Add sodium metabisulfite solution, then 20% ammonia solution and acetone and concentrate. After washing with 100 mL of chloroform, the aqueous phase is recovered and then neutralized with acetic acid. Extraction with 200 mL of chloroform is carried out twice. After separating the aqueous phase, the organic phase is dried and concentrated under reduced pressure. 20.1 g of the desired enantiomer is obtained with an enantiomeric excess of more than 65% (yield 64%). When multiple crystallizations are performed in a DMF / ethyl acetate mixture, this enantiomer is obtained with an enantiomeric excess greater than 99%.

Claims (29)

A process for the enantioselective preparation of a sulfoxide derivative or a basic salt thereof, using an oxidant in the presence of a tungsten or vanadium based catalyst and a chiral ligand and having the following general formula (I):
_{A-CH 2 -S-B (} I)
[Wherein A is a pyridyl nucleus which is variously substituted and B is a heterocyclic residue having a benzimidazole or imidazopyridyl nucleus]
A process, characterized in that the enantioselective oxidation of the sulfide of is followed by chlorination with a base, if necessary, to give the sulfoxide A—CH ₂ —SO—B (Ia).   In general formula (I), a pyridyl group or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, one or more halogen atoms One selected from a methyl or ethyl group, an amino, an alkylamino or a dialkylamino group, wherein the alkyl component is straight or branched and has 1 to 5 carbon atoms substituted by Or a pyridyl group having a plurality of substituents; B is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, if necessary, and a straight chain of 1 to 6 carbon atoms. 2. The heterocycle according to claim 1, characterized in that it represents a heterocycle selected from benzimidazole or imidazo- [4,5-b] -pyridyl groups substituted by chain or branched chain alkoxy groups. Law.   3. A method according to claim 2, characterized in that the A and B groups are substituted at one or more carbon atoms by methyl, ethyl, methoxy or trihalogenomethyl groups.   4. A method according to claim 3, characterized in that A is a 2-pyridyl group substituted by one or more methyl, ethyl, methoxy or trifluoromethyl groups.   A is a 4-methoxy-3,5-dimethyl-2-pyridyl group and B is a 5-methoxy-1H-benzimidazolyl or 5-methoxy-imidazol- [4,5-b] -pyridyl group. The method according to claim 3, characterized in that:   A method according to any of the preceding claims, characterized in that the enantiomer obtained is salified by reacting with a basic inorganic reagent containing an alkali or alkaline earth counterion.   The method of claim 6, wherein the salt is a sodium, potassium, lithium, magnesium or calcium salt.   The method according to any one of claims 1 to 7, wherein the oxidizing agent is a peroxide or a hydroperoxide. Wherein the oxidizing agent is hydrogen peroxide, urea _-H 2 _O 2 (UHP) or cumene or t- butyl hydroperoxide, The method of claim 8.   10. A process according to any preceding claim, wherein the catalyst is (V) an oxo-vanadium complex or a derivative of tungsten.   11. The method of claim 10, wherein the complex or derivative is prepared from tungsten trioxide, vanadium acetylacetonate or vanadium sulfate.   12. The method according to claim 1, wherein the catalyst is based on vanadium and the ligand is tridentate. Said ligand has the following general formula (II):
_{RO-CR 1 R 2 -CR 3} R 4 -NR 5 R 6
[In the above formula,
R is a hydrogen atom or a straight or branched alkyl group of 1 to 6 carbon atoms or an aryl or heteroaryl group;
R ₁ to R ₄ may be the same or different and optionally have a straight chain of 1 to 6 carbon atoms having heteroatoms such as sulfur, nitrogen and oxygen and / or optionally substituted with an amino group or Represents a branched alkyl group; an aryl group; an alkylaryl group; an alkoxycarbonyl group; a heteroaryl group or a heterocycle; a heteroarylalkyl or heterocycloalkyl group, provided that the ligand is one or two asymmetric centers R ₁ must not be the same as R ₂ and / or R ₃ must not be the same as R ₄ ;
R ₁ and R ₂ may both represent a carbonyl group C═O;
R ₁ and R ₃ or R ₂ and R ₄ are both carbocycles having 5 or 6 carbon atoms, or bicyclic rings having 9 to 10 carbon atoms and one of the rings may be aromatic May form a system;
R ₄ and R ₅ may be the same or different and may form a 5- or 6-membered heterocycle having a nitrogen atom;
R ₅ and R ₆ may be the same or different and represent a straight-chain or branched alkyl group having 1 to 6 carbon atoms or a 5- or 6-membered carbocycle, or a heterocycle with a nitrogen atom bonded thereto. Forming a ring; or
R ₅ and R ₆ together with nitrogen represent a —N═CHAr double bond, where Ar may be substituted with 1 to 3 groups, preferably an aryl residue having a hydroxyl group Is]
The method according to claim 1, wherein the method is represented by:   The process according to claim 13, characterized in that Ar is a 2'-hydroxyphenyl group optionally substituted at the aryl group. R ₁ and R ₃ or R ₂ and R ₄ represent a hydrogen atom, wherein R ₂ and R ₄ or R ₁ and R ₃ are each a linear or branched alkyl group having 1 to 6 carbon atoms Forming a carbocyclic ring which is an aryl group, both having 5 or 6 carbon atoms, or a bicyclic system having 9 or 10 carbon atoms, one of which may be aromatic. 15. A method according to claim 13 or 14, characterized. The aryl group is selected from a phenyl group, a naphthyl group, a tetrahydronaphthyl group, an indanyl group, and a binaphthyl group, wherein the aryl group is a hydroxyl group, a linear or branched group having 1 to 4 carbon atoms. 16. The alkyl group according to claim 13, which may be substituted with 1 to 3 substituents selected from a branched alkyl group, a nitro group, a (C ₁ -C ₄ ) alkoxy group and a halogen atom. The method according to any of the above. The ligand of formula (II) is:
Amino-alcohols of formula (III)

[Wherein R ₁ , R ₂ , R ₃ and R ₄ are defined as in any of claims 13 to 16],
Amino-ether of formula (IV)

[Wherein R, R ₁ , R ₂ , R ₃ and R ₄ are defined as in any of claims 13 to 16],
Amino acids of formula (V)

[Wherein R ′ has the definition of R ₃ or R ₄ according to any of claims 13 to 16],
Amino-esters of the formula (VI)

Wherein R ′ has the definition of R ₃ or R ₄ according to any of claims 13 to 16, and R ″ is the definition of R according to any of claims 13 to 16. 17. The method according to any one of claims 13 to 16, characterized in that the method is selectively derived from.   The amino alcohols of the formula (III) are L- or D-valinol, Rt-leucinol, St-leucinol and (1S, 2R)-(−)-or (1R, 2S)-(+)-1 -Selected from amino-2-indanol, the amino acid of formula (V) is L-valine or D-valine, L-phenylalanine or D-phenylalanine, L-methionine or D-methionine, L-histidine or D-histidine, The method according to claim 17, characterized in that it is selected from L-lysine or D-lysine. An amino-alcohol, amino-ether, amino acid or amino-ester of the formula (III), (IV), (V) and (VI) as defined in claim 17 or 18, respectively, is converted to salicylic acid of the formula (VII) Aldehyde:

[Wherein R ₇ is independently of each other from a hydroxyl group, a linear or branched alkyl group containing 1 to 4 carbon atoms, a nitro group, a (C ₁ -C ₄ ) alkoxy group and a halogen atom. The method according to any one of claims 13 to 18, characterized in that the ligand of formula (II) is obtained by reacting with 1 to 2 selected substituents.   Catalysts prepared from vanadium acetylacetonate and ligands derived from amino-alcohols or amino-ethers of the formula (III) or (IV) respectively defined in claim 17 or 18 are used, 20. A method according to any one of claims 13-19. The ligand of formula (II) is derived from an amino alcohol of formula (III) as defined in claim 17, wherein
R ₅ and R ₆ together with the nitrogen atom represent a double bond —N═CHAr, where Ar is an aryl group comprising 1 to 3 substituents and at least one hydroxyl group, Ar being , Preferably a phenyl group,
R ₁ and R ₃ , or R ₂ and R ₄ represent a hydrogen atom, wherein R ₂ and R ₄ or R ₁ and R ₃ are each independently a straight chain of 1 to 6 carbon atoms Or a branched alkyl group, preferably t-butyl, both carbocyclic rings of 5 to 6 carbons or bicyclic rings having 9 or 10 carbon atoms, one of which may be aromatic 21. Process according to claim 20, characterized in that it forms a system, preferably indanyl.   Use of a catalyst prepared from vanadium sulfate and a ligand derived from an amino acid or amino-ester of formula (V) or (VI) as defined in claim 17 or 18, respectively. The method according to any of the above.   The ligand is 2,4-di-t-butyl-6- [1-R-hydroxymethyl-2-methyl-propylimino) -methyl] phenol, 2,4-di-t-butyl-6- [1-S-hydroxymethyl-2-methyl-propylimino) -methyl] -phenol, (1R, 2S) -1- [2-hydroxy-3,5-di-t-butyl-benzylidene) -amino]- Indan-2-ol or (1S, 2R) -1- [2-hydroxy-3,5-di-tert-butyl-benzylidene) -amino] -indan-2-ol The method according to any one of 1 to 21.   24. A method according to claim 23, characterized in that the ligand is in the form of an acetonitrile solution.   2,4-di-t-butyl-6- [1-R-hydroxymethyl-2-methyl-propylimino) -methyl] -phenol or (1R, 2S) -1- [2-hydroxy-3,5- By using a vanadium-based catalyst in the form of an acetonitrile solution with a ligand consisting of di-t-butyl-benzylidene) -amino] -indan-2-ol, 5-methoxy-2-[[(4-methoxy- Enantioselective oxidation of 3,5-dimethyl-2-pyridyl) methyl] thio] imidazo [4,5-b] pyridine was performed to give (−)-5-methoxy-2-[[(4-methoxy- 3,5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4,5-b] pyridine, wherein the sulfides are methylene chloride or acetone or - characterized in that it is in the form of a methylpyrrolidinone solution, The method of claim 23 or 24. The catalyst is a tungsten derivative, and the ligand is hydroquinine 2,5-diphenyl-4,6-pyridinyl diether (DHQ) ₂ -PYR or hydroquinidine 2,5-diphenyl-4,6-pyri. 12. A process according to claim 10 or 11, characterized in that it is dinyl diether (DHQD) _2- PYR. 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] imidazo [4] with hydrogen peroxide in the presence of tungsten trioxide and (DHQD) _2- PYR. , 5-b] pyridine was subjected to enantioselective oxidation to give (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4 , 5-b] pyridine is obtained.   The method according to claim 1, wherein the oxidation reaction is carried out in a solvent, in a neutral or weakly basic medium.   Said solvent comprises a sulfide-specific solvent and a ligand-specific solvent selected from methanol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, acetone, chloroform, dimethylformamide and N-methylpyrrolidinone alone or in mixed form. 29. A process according to claim 28, characterized in that it is a solvent mixture and the base is a tertiary amine selected from pyridine, di-isopropyl-ethylamine and triethylamine.